New synthesis of SKF 89976A

Article abstract of DOI:10.1016/j.tetlet.2006.06.156

Substituted 4,4-diaryl-3-butenyl-1-amines are synthesized in nearly 34-47% overall yields starting from 3-hydroxypiperidine by the regioselective Baeyer-Villiger lactonization, Grignard addition and elimination sequence. This facile strategy was also used

Full text of DOI:10.1016/j.tetlet.2006.06.156

Tetrahedron Letters 47 (2006) 6389–6392
New synthesis of SKF 89976A
Meng-Yang Chang,a,* Si-Yun Wanga and Chun-Li Paib
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 19 May 2006; accepted 29 June 2006
Available online 25 July 2006
Abstract—Substituted 4,4-diaryl-3-butenyl-1-amines are synthesized in nearly 34–47% overall yields starting from 3-hydroxypiperi-
dine by the regioselective Baeyer–Villiger lactonization, Grignard addition and elimination sequence. This facile strategy was also
used to synthesize racemic SKF 89976A.
ꢀ 2006 Elsevier Ltd. All rights reserved.
OH
Ar
Ar
1. Introduction
Ar
Ar
Ar
Ar
These substituted and functionalized 4,4-diaryl-3-buten-
yl-1-amines and their analogs are often used as key
intermediates for the synthesis of GABA-uptake inhibi-
tors with potential biological activities of different clas-
ses.1 The compounds with different N-substituted
diarylbutenyl group display anti-convulsant activities
such as compound SKF 89976A, SKF 100300A, SKF
100561 and tiagabine.1,2 Development of a general pro-
cedure for 4,4-diaryl-3-butenyl-1-amine provides an
expedient entry point.2
H N
2
our work
Ar C(=O)
2
O
Li
N
O
Li
N
Ph
Ts
Figure 1.
Basically, the adopted strategies can be summarized in
Lewis acid-catalyzed,3,4 for example, tin(II) triflate,
ytterbium(III) triflate, boron trifluoride etherate, hydro-
gen bromide and palladium(II)-promoted5 cyclopropane
rearrangement and organolithium addition of N-(2-
2. Results and discussion
For synthesizing compounds 1a–f, 3-hydroxypiperidine
(2) was chosen as the starting material as shown in
Scheme 1.7 Compounds 1a–f were prepared by the
five-step protocol and described as follows: (i) N-tosyl-
ation of compound 2 with p-toluenesulfonyl chloride
and triethylamine at 0 ꢁC for 1 h, (ii) oxidation of the
resulting 1-tosylpiperidin-3-ol with Jones reagent at 0 ꢁC
for 15 min, (iii) specific regioselective Baeyer–Villiger
lactonization8 of 1-tosylpiperidin-3-one (3) at rt for 10 h,
(iv) Grignard addition of 3-tosyl[1,3]oxazepan-7-one
(4) with different arylmagnesium bromide reagents (a,
Ar = C6H5; b, Ar = 2-CH3C6H4; c, Ar = 2-CH3OC6H4;
d, Ar = 3-CH3OC6H4; e, Ar = 4-CH3OC6H4; f,
Ar = 3,4-CH2O2C6H3) at À78 ꢁC for 2 h, (v) dehydration
of the resulting tertiary alcohols with boron trifluoride
etherate at 0 ꢁC for 15 min.9
chloroethyl)benzamide
(Fig. 1).
with
1,1-diarylmethanone6
Herein, we want to develop an easy and straightfor-
ward strategy to substituted 4,4-diaryl-3-butenyl-1-
tosylamines 1a–f via key regioselective Baeyer–Villiger
lactonization of 1-tosylpiperidin-3-one with m-chloro-
peroxybenzoic acid.
Keywords: 3-Hydroxypiperidine; Baeyer–Villiger lactonization;
3-Tosyl-[1,3]oxazepan-7-one; 4,4-Diaryl-3-butenyl-1-amines.
*
Corresponding author. Tel.: +886 7 5919464; fax: +886 7 5919348;
e-mail: mychang@nuk.edu.tw
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.156

6390
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 6389–6392
C H
O
C H
6 5
6
5
1) Na(Hg), MeOH
OH
O
1) TsCl, Et N
3
MCPBA
(89%)
C H
C H
6 5
O
6
5
CO Me
2
2) NaH,
Br
CO H
2) Jones ox.
(two-step 88%)
2
NH
Ts
N
N
H
N
N
then 6N HCl,
6
(two steps 63%)
Ts
Ts
2
3
4
SKF 89976A (5)
1a
Ar
Ar
Scheme 2.
1a, Ar=C H (60%)
6
5
1) ArMgBr
1b, Ar=2-CH C H (51%)
3
6 4
1c, Ar=2-CH OC H (50%)
3
6 4
the primary amine. SKF 89976A (5) was afforded by the
alkylation of the resulting amine with compound 612 and
subsequently followed by hydrolysis (Scheme 2).
2) BF -OEt
3
2
1d, Ar=3-CH OC H (51%)
3
6 4
NH
Ts
1e, Ar=4-CH OC H (43%)
3
6 4
1f, Ar=3,4-CH O C H (52%)
2
2 6 4
1
Scheme 1.
3. Conclusion
In summary, we present an easy and straightforward
synthesis of compounds 1a–f by the regioselective Bae-
yer–Villiger lactonization, Grignard addition and elimi-
nation sequence. This facile strategy was also used to
synthesize SKF 89976A (5).
While poring over the related literature of regioselective
Baeyer–Villiger ring expansion reaction, we found that
Young and co-workers had developed copper(II) ace-
tate-mediated ring expansion of 4-ketoprolines with m-
chloroperoxybenzoic acid in modest yield.10 The unique
synthetic methodology was similar to our results. How is
the regioselective Beayer–Villiger lactonization initiated?
According to literature reports, the most likely explana-
tion would be that it is controlled by involvement of the
nitrogen lone pair on substituted pyrrolidin-4-one.10
Acknowledgements
The authors would like to thank the National Science
Council of the Republic of China for financial support.
We also found that reaction of 1-tosylpiperidin-4-one
with m-chloroperoxybenzoic acid under the similar con-
ditions was unsuccessful. The starting material was recy-
cled and the ring-expanded product was not obtained.
In comparison with the regioselectivity of Beayer–
Villiger process of 1-tosylpiperidin-4-one, we believe
the amino group can play an important factor to initiate
the ring expansion. During the process, the 4-
tosyl[1,4]oxazepan-2-one framework was not observed.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.156.
References and notes
For the two-step transformation of Grignard addition
and dehydration, substituted compounds 1a–f were ob-
tained in 43–60% yield from compound 4. For the intro-
duction of different 4,4-diaryl group of compounds 1a–f,
the present strategy exhibited a facile methodology in
comparison with the reported literature.3 The total syn-
thetic procedure could be monitored by TLC until the
reaction was complete within a working day. During
separation of compound 1e, 2,2-bis(4-methoxyphenyl)-
1-tosylpyrrolidine (ca. 10%) was the yield.11 Silica gel-
mediated intramolecular cyclization of compound 1e
by the 4-methoxy group was provided. The compounds
with other electron donating groups did not show the
similar phenomena. For the 4,4-dialkyl group, some
complex and inseparated products having different cis
and trans three substituted olefinic isomers were affor-
ded in the synthesis of 4,4-diethylbutenyl-1-amine.
1. (a) Zhao, X.; Hoesl, C. E.; Hoefner, G. C.; Wanner, K. T.
Eur. J. Med. Chem. Chim. Ther. 2005, 40, 231; (b) Glennon,
R. A.; Ismaiel, A. M.; Ablordeppey, S.; El-Ashmawy, M.;
Fisher, J. B. Bioorg. Med. Chem. Lett. 2004, 14, 2217; (c)
Kehler, J.; Stensboel, T. B.; Krogsgaard-Larsen, P. Bioorg.
Med. Chem. Lett. 1999, 9, 811; (d) Caldirola, P.; Zandberg,
P.; Mannhold, R.; Timmerman, H. Eur. J. Med. Chem.
Chim. Ther. 1993, 28, 555; (e) Gualtieri, F.; Teodori, E.;
Bellucci, C.; Pesce, E.; Piacenza, G. J. Med. Chem. 1985,
28, 1621; (f) Falch, E.; Krogsgaard-Larsen, P. Eur. J. Med.
Chem. Chim. Ther. 1991, 26, 69; (g) Hoefle, M. L.; Blouin,
L. T.; Fleming, R. W.; Hastings, S.; Hinkley, J. M.;
Hinkley, ; Mertz, T. E.; Steffe, T. J.; Stratton, C. S. J. Med.
Chem. 1991, 34, 12; (h) Varoli, L.; Burnelli, S.; Budriesi, R.;
Guarnieri, A.; Chiarini, A.; Recanatini, M. Med. Chem.
Res. 1996, 6, 571.
2. For synthesis of SKF 89976A and its analogs, see: (a) Ali,
F. E.; Bondinell, W. E.; Dandridge, P. A.; Frazee, J. S.;
Garvey, E.; Girard, G. R.; Kaiser, C.; Ku, T. W.; Lafferty,
J. J.; Moonsammy, G. I.; Oh, H.-J.; Rush, J. A.; Setler, P.
E.; Stringer, O. D.; Venslavsky, J. W.; Volpe, B. W.;
Yunger, L. M.; Zirklet, C. L. J. Med. Chem. 1985, 28, 653;
(b) Dhar, T. G. M.; Nakanishi, H.; Borden, L. A.;
Gluchowski, C. Bioorg. Med. Chem. Lett. 1996, 6, 1535;
(c) N’Goka, V.; Schlewer, G.; Linget, J. M.; Chambon, J.
P.; Wermuth, C. G. J. Med. Chem. 1991, 34, 2547; (d)
In view of the experimental simplicity, the preparation
of compound 1a was also conducted in a multigram
scale (10 mmol) with 55% overall yield of two steps.
With these results in hand, the next focus was to exam-
ine the synthesis of racemic SKF 89976A (5). Desulfona-
tion of the compound 1a with sodium amalgam yielded

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 6389–6392
6391
Suzdak, P. D. Drugs Future 1993, 18, 1129, and references
cited therein.
3. (a) Chen, Y.; Shi, M. J. Org. Chem. 2004, 69, 426; (b) Shi,
M.; Xu, B. Org. Lett. 2002, 4, 2145; (c) Huang, J. W.; Shi,
M. Synlett 2004, 2343.
4. (a) Rigby, J. H.; Danca, D. M.; Horner, J. H. Tetrahedron
Lett. 1998, 39, 8413; (b) Linkert, F.; Laschat, S.; Kotila,
S.; Fox, T. Tetrahedron 1996, 52, 955.
5. (a) Nuske, H.; Notlemeyer, M.; de Meijere, A. Angew.
Chem., Int. Ed. 2001, 40, 3411; (b) Nakamura, I.; Oh, B. H.;
Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001,
40, 1298; (c) Oh, B.-H.; Nakamura, I.; Saito, S.; Yama-
moto, Y. Tetrahedron Lett. 2001, 42, 6203; (d) Fournet, G.;
Balme, G.; Gore, J. Tetrahedron 1988, 44, 5809; (e) Brase,
S.; de Meijere, A. Angew. Chem., Int. Engl. 1995, 34, 2545;
(f) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 1999, 38, 3365; (g) Lautens, M.;
Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
product under reduced pressure. Purification on silica gel
(hexane/ethyl acetate = 4/1–2/1) afforded compounds
1a–f. For compound 1a: 1H NMR (500 MHz, CDCl3)
d 7.70 (d, J = 8.5 Hz, 2H), 7.38–7.23 (m, 8H), 7.16–7.10
(m, 4H), 5.91 (t, J = 7.5 Hz, 1H), 4.36 (t, J = 6.0 Hz, 1H),
3.05 (q, J = 7.0 Hz, 2H), 2.42 (s, 3H), 2.28 (q, J = 7.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 144.81, 143.35,
141.88, 139.38, 136.84, 129.68 (2·), 129.64 (2·), 128.36
(2·), 128.12 (2·), 127.33, 127.26, 127.19 (2·), 127.06 (2·),
124.41, 43.02, 29.81, 21.52; HRMS (ESI) m/z calcd for
C23H24NO2S (M++1) 378.1528, found 378.1529. For
compound 1b: 1H NMR (500 MHz, CDCl3) d 7.68 (d,
J = 8.5 Hz, 2H), 7.27–7.03 (m, 10H), 5.63 (t, J = 7.5 Hz,
1H), 4.30 (t, J = 6.0 Hz, 1H), 3.03 (q, J = 7.0 Hz, 2H),
2.42 (s, 3H), 2.22 (s, 3H), 2.19 (q, J = 7.0 Hz, 2H), 2.07 (s,
3H); 13C NMR (125 MHz, CDCl3) d 143.93, 143.35,
141.76, 139.23, 136.81, 136.10, 135.30, 130.81, 130.43,
130.28, 129.74, 129.66 (2·), 128.48, 127.26, 127.02 (2·),
126.93, 125.52, 125.46, 42.85, 29.71, 21.50, 20.99, 19.96;
HRMS (ESI) m/z calcd for C25H28NO2S (M++1)
406.1841, found 406.1844. For compound 1c: 1H NMR
(500 MHz, CDCl3) d 7.64 (d, J = 8.0 Hz, 2H), 7.30–7.20
(m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.05 (td, J = 2.0, 8.0 Hz,
2H), 6.96–6.91 (m, 2H), 6.86 (d, J = 7.5 Hz, 2H), 5.57 (t,
J = 7.5 Hz, 1H), 5.33 (t, J = 5.0 Hz, 1H), 3.88 (s, 3H), 3.71
(s, 3H), 3.00 (q, J = 5.5 Hz, 2H), 2.36 (s, 3H), 2.12 (q,
J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 156.82,
155.94, 142.84, 138.20, 136.70, 131.85, 130.85, 130.26,
129.37 (2·), 129.32, 129.10, 128.37, 128.13, 127.11 (2·),
120.58, 120.29, 111.35, 110.96, 55.69, 55.54, 41.96, 29.07,
21.40; HRMS (ESI) m/z calcd for C25H28NO4S (M++1)
438.1739, found 438.1738. For compound 1d: 1H NMR
(500 MHz, CDCl3) d 7.69 (d, J = 8.0 Hz, 2H), 7.28–7.24
(m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 6.86 (ddd, J = 1.0, 2.5,
8.0 Hz, 1H), 6.79–6.76 (m, 2H), 6.73 (dd, J = 2.0, 2.0 Hz,
1H), 6.69 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 1.0, 2.0 Hz,
1H), 5.92 (t, J = 7.5 Hz, 1H), 4.57 (t, J = 6.0 Hz, 1H), 3.78
(s, 3H), 3.76 (s, 3H), 3.04 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H),
2.26 (q, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d
159.54, 159.41, 144.38, 143.35, 143.13, 140.68, 136.84,
129.69 (2·), 129.38, 129.05, 127.04 (2·), 124.71, 122.03,
119.73, 115.00, 113.13, 112.90, 112.47, 55.21, 55.20, 42.99,
29.83, 21.49; HRMS (ESI) m/z calcd for C25H28NO4S
6. Barluenga, J.; Foubelo, F.; Fananas, F. J.; Yus, M.
Tetrahedron 1989, 45, 2183.
7. (a) Chang, M. Y.; Hsu, R. T.; Chen, H. P.; Lin, P. J.
Heterocycles 2006, 68, 1173; (b) Chang, M. Y.; Lin, C. Y.;
Wu, T. C. Tetrahedron Lett. 2006, 47, 5445; (c) Chang, M.
Y.; Lin, C. Y.; Pai, C. L. Tetrahedron Lett. 2006, 47, 2565;
(d) Chang, M. Y.; Pai, C. L.; Lin, C. Y. Tetrahedron Lett.
2006, 47, 3641; (e) Chang, M. Y.; Pai, C. L.; Kung, Y. H.
Tetrahedron Lett. 2006, 47, 855; (f) Chang, M. Y.; Pai, C.
L.; Kung, Y. H. Tetrahedron Lett. 2005, 46, 8463.
8. Synthesis of compound 4 is as follows: A solution of m-
chloroperoxybenzoic acid (11.5 g, 75%, 50.0 mmol) in
dichloromethane (10 mL) was added to a solution of
compound 3 (10.12 g, 40.0 mmol) and sodium carbonate
(6.36 g, 60.0 mmol) in dichloromethane (200 mL) at 0 ꢁC.
The reaction mixture was stirred at rt for 6 h. Saturated
sodium carbonate solution (40 mL) was added to the
reaction mixture and the solvent was concentrated under
reduced pressure. The residue was extracted with ethyl
acetate (3 · 100 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on
silica gel (hexane/ethyl acetate = 4/1–2/1) afforded com-
pound 4 (9.58 g, 89%). 1H NMR (300 MHz, CDCl3) d 7.79
(d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.45 (s, 2H),
3.63 (t, J = 5.4 Hz, 2H), 2.66–2.62 (m, 2H), 2.42 (s, 3H),
1.44–1.36 (m, 2H); 13C NMR (75 MHz, CDCl3) d 173.29,
144.69, 137.14, 130.28 (2·), 127.76 (2·), 76.04, 49.51,
33.86, 22.28, 21.84; HRMS (ESI) m/z calcd for
C12H16NO4S (M++1) 270.0800, found 270.0802.
9. A representative procedure of compounds 1a–f is as
follows: A solution of arylmagnesium bromide (3.0 mL,
1.0 M in tetrahydrofuran, 3.0 mmol) was added to a
stirred solution of compound 4 (270 mg, 1.0 mmol) in
tetrahydrofuran (10 mL) at À78 ꢁC. The reaction mixture
was stirred at rt for 6 h. Water (1 mL) was added to the
reaction mixture and the mixture was filtered through a
short plug of Celite. The filtrate was concentrated under
reduced pressure. The residue was extracted with ethyl
acetate (3 · 30 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Without further
purification, a solution of boron trifluoride etherate
(1 mL) was added to a stirred solution of the crude
product in dichloromethane (20 mL) at 0 ꢁC. The reaction
mixture was stirred at rt for 15 min. Saturated sodium
bicarbonate solution (10 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with ethyl acetate
(3 · 30 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
1
(M++1) 438.1739, found 438.1740. For compound 1e: H
NMR (500 MHz, CDCl3) d 7.69 (d, J = 8.0 Hz, 2H), 7.26
(d, J = 8.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.02
(d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.79
(d, J = 9.0 Hz, 2H), 5.75 (t, J = 7.5 Hz, 1H), 4.34 (t,
J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.04 (q,
J = 7.0 Hz, 2H), 2.42 (s, 3H), 2.27 (q, J = 7.0 Hz, 2H); 13
C
NMR (125 MHz, CDCl3) d 158.99, 158.71, 143.92, 143.32,
136.56, 134.98, 131.84, 130.82 (2·), 129.66 (2·), 128.39
(2·), 127.06 (2·), 122.36, 113.68 (2·), 113.44 (2·), 55.27,
55.23, 43.15, 29.75, 21.51; HRMS (ESI) m/z calcd for
C25H28NO4S (M++1) 438.1739, found 438.1740. For 2,2-
Bis(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)pyrroli-
1
dine: H NMR (500 MHz, CDCl3) d 7.25–7.22 (m, 4H),
7.00 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.78–
6.75 (m, 4H), 3.83 (s, 6H),3.81 (t, J = 7.0 Hz, 2H), 2.52 (t,
J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.84–1.79 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 158.48 (2·), 141.89, 138.47,
134.87 (2·), 130.48 (4·), 128.64 (2·), 128.54 (2·), 112.62
(4·), 75.12, 55.28 (2·), 50.40, 45.51, 22.35, 21.40; HRMS
(ESI) m/z calcd for C25H28NO4S (M++1) 438.1739, found
438.1742. For compound 1f: 1H NMR (500 MHz, CDCl3)
d 7.71 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.79
(d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.65 (d,
J = 1.5 Hz, 1H), 6.61 (dd, J = 1.5, 8.0 Hz, 1H), 6.55 (d,
J = 8.0 Hz, 1H), 6.54 (s, 1H), 5.98 (s, 2H), 5.93 (s, 2H),

6392
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 6389–6392
5.72 (t, J = 7.5 Hz, 1H), 4.41 (t, J = 6.0 Hz, 1H), 3.02 (q,
J = 6.5 Hz, 2H), 2.42 (s, 3H), 2.26 (q, J = 7.0 Hz, 2H); 13
11. (a) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am.
C
Chem. Soc. 1995, 117, 10449; (b) Borg, R. M.; Heucke-
roth, R. O.; Lan, A. J. Y.; Quillan, S. L.; Mariano, P. S. J.
Am. Chem. Soc. 1987, 109, 2728; (c) Maryanoff, B. E.;
McComsey, D. F.; Gardocki, J. F.; Shank, R. P.;
Costanzo, M. J.; Notey, S. O.; Schneider, C. R.; Setler,
P. E. J. Med. Chem. 1987, 30, 1433.
NMR (125 MHz, CDCl3) d 147.57, 147.52, 146.96, 146.74,
143.88, 143.39, 136.84, 136.47, 133.17, 129.68 (2·), 127.05
(2·), 123.23, 123.03, 121.11, 110.05, 108.17, 107.81,
107.55, 101.04 (2·), 43.05, 29.82, 21.49; HRMS (ESI) m/
z
calcd for C25H24NO6S (M++1) 466.1324, found
466.1326.
12. (a) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538;
(b) Alanine, A. I. D.; Fishwick, C. W. G.; Jones, A. D.;
Mitchell, M. B. Tetrahedron Lett. 1989, 30, 5653; (c)
Alanine, A. I. D.; Fishwick, C. W. G. Tetrahedron Lett.
1989, 30, 4443.
10. (a) Burtin, G.; Corringer, P. J.; Hitchcock, P. B.; Young,
D. W. Tetrahedron Lett. 1999, 40, 4275; (b) Burtin, G.;
Corringer, P. J.; Young, D. W. J. Chem. Soc., Perkin
Trans. 1 2000, 3451.